Background/Purpose:

Genetic factors have been identified that may be associated with the development and severity of rheumatoid arthritis (RA), disease progression, or response to treatment. In-depth knowledge about RA susceptibility genes may thus prove useful for the development of future diagnostic tests or personalized therapeutics. Frequencies from previously investigated RA susceptibility gene polymorphisms from patients enrolled in the OPTIMA trial were compared to a control database to identify genetic risk factors for RA.

Methods: OPTIMA was a 78-week, multicenter, randomized study designed to assess adalimumab plus methotrexate therapy in early RA patients.(1) Of 1032 patients, genetic analysis was conducted on 921 patients who signed an additional informed consent for genetic analyses. Frequency rates for 168 identified RA susceptibility alleles from 88 genes were compared to the European cohort of the 1000 Genomes Project as a reference control.(2) Genotypic variants were assayed using the Illumina BeadXpress GoldenGate Assay. The largest deviations in the OPTIMA minor allele frequencies (MAFs), those > 0.05 compared to the control, were further investigated. Logistic regression was used to calculate odds ratios (OR) for RA susceptibility. Association of alleles with 28-joint count disease activity score (DAS28) and age were conducted using ANOVA comparing the OPTIMA cohort with the control cohort.

Results: The majority of single nucleotide polymorphism (SNP) MAFs from the OPTIMA study did not deviate > 0.05 from MAFs reported in the European cohort from the 1000 Genomes Project. Within known RA susceptibility genes or those with treatment response, 7 of 63 SNPs previously investigated as being associated with increased RA risk deviated > 0.05 from reference controls in OPTIMA patients and were investigated further; 11 SNPs that had not been previously associated with RA susceptibility had MAF differences > 0.05 comparing OPTIMA with the reference control. The BTLA SNP rs9288952 G allele displayed the highest OR for RA risk, 3.60 (95% CI, 2.49 – 5.20), was weakly associated with higher baseline DAS28, and also associated with patient age (mean ages were 50.9, 49.0, and 44.3 for genotypes A/A, A/G, and G/G, respectively), suggesting a potential association with onset at earlier or later age. STAT4 rs7574865 minor allele homozygosity was associated with higher baseline DAS28 scores. Of the previously unidentified RA susceptibility gene SNPs, only PDZD2 rs1532269 was significantly associated with higher baseline DAS28 scores.

Conclusion: Genes identified with increased RA risk have known roles in immune responses including mediation of lymphocyte signaling, proliferation, and differentiation. The MAFs of 18 gene SNPs in the OPTIMA study differed from a healthy control population; further investigation into these SNPs will clarify their role in RA susceptibility and disease progression.

	Gene	SNP	1000 Genomes MAF	OPTIMA MAF	Difference Between MAFs	Odds Ratio (95% CI)
Previously Investigated RA Susceptibility Gene SNPs	BTLA	rs9288952	0.04	0.15	0.11	3.60 (2.49 – 5.20)***
	FNDC1/TAGAP	rs394581	0.32	0.26	0.06	0.75 (0.62 – 0.90)**
	HLA-DPB1/HLA-DPB2	rs3117213	0.26	0.18	0.08	0.62 (0.51 – 0.76)***
	HLA-DQB1/HLA-DQA2	rs6457617	0.45	0.33	0.12	0.62 (0.52 – 0.73)**
	IL23R/IL12RB2	rs1495965	0.49	0.42	0.07	0.76 (0.64 – 0.90)***
	PTPN22	rs2476601	0.01	0.13	0.12	1.31 (0.99 – 1.72)#
	STAT4	rs7574865	0.23	0.29	0.06	1.37 (1.13 – 1.67)**
Previously Unidentified RA Susceptibility Gene SNPs	FAM167A/BLK	rs13277113	0.33	0.25	0.08	1.49 (1.23 – 1.81)***
	HLA-DPB1	rs3135021	0.36	0.28	0.08	1.48 (1.23 – 1.78)***
	NOS3	rs2070744	0.33	0.41	0.07	0.73 (0.61 – 0.87)***
	PDZD2	rs1532269	0.44	0.37	0.07	1.35 (1.14 – 1.61)***
	PTPN22	rs2488458	0.34	0.27	0.07	1.41 (1.17 – 1.70)***
	PTPRC	rs1326279	0.38	0.31	0.07	1.36 (1.13 – 1.63)***
	PTPRC	rs12144388	0.37	0.31	0.06	1.31 (1.09 – 1.57)**
	STAT4	rs12463658	0.47	0.40	0.07	1.35 (1.14 – 1.60)***
	STAT4	rs3024877	0.37	0.30	0.07	1.36 (1.14 – 1.64)***
	STAT4	rs1031509	0.20	0.27	0.07	0.70 (0.57 – 0.85)***
	STAT4	rs11693480	0.46	0.40	0.06	1.29 (1.08 – 1.53)**
MAF, minor allele frequency; SNP, single nucleotide polymorphism. ** and *** denote statistical significance at the p < 0.01 and 0.001 levels, respectively. #significant when homozygous for the minor allele.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/application-of-a-multiplex-gene-polymorphism-assay-for-variants-associated-with-rheumatoid-arthritis-susceptibility-results-of-168-single-nucleotide-polymorphisms-in-the-optima-study/